scholarly journals P09.07 An immune modulatory vaccine targeting CCL22 promotes anti-tumor immunity

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A55.1-A55
Author(s):  
I Lecoq ◽  
KL Kopp ◽  
R Christensen ◽  
E Martinenaite ◽  
AW Pedersen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Modulation ◽  
Ex Vivo ◽  
Mouse Tumor ◽  
Peptide Vaccines ◽  
Tumor Models ◽  
Cancer Immunity ◽  
Anti Cancer ◽  
Part Time

BackgroundCCL22 is a macrophage-derived chemokine that exerts immunosuppressive functions by the recruitment of regulatory T cells (Treg) through the CCL22/CCR4 axis. It has been described to play a key role in the suppression of anti-cancer immunity in different cancer types including ovarian, breast, or pancreatic cancer and is thought to promote the suppression of anti-cancer immunity by Treg recruitment. Recently, we described that CCL22-specific T cells generated from cancer patients can kill CCL22-expressing tumor cells and directly influence the level of CCL22 in vitro.1 In this study, we provide PoC data for a CCL22-targeting vaccine by assessing the immunotherapeutic efficacy of this approach in syngeneic mouse tumor models.Materials and MethodsPeptide vaccines that induce expansion of CCL22-specific T cells were identified by measurement of vaccine-induced ex vivo response (IFNγ ELISpot) in BALB/c and C57BL/6 mice. The antitumor efficacy was evaluated in CT26, Pan02 and B16 syngeneic models. To investigate the vaccine’s mode of action, the tumor immune infiltration was analyzed through flow cytometry and qPCR.ResultsVaccination with CCL22-specific peptide vaccines induced expansion of primarily CD8+, CCL22-specific T cell responses (assessed by ex vivo IFNγ ELISpot). Treatment with CCL22 vaccines reduced tumor growth and increased survival in CT26, Pan02 and B16 tumor models. Assessment of gene expression in the tumors indicated that vaccination leads to a reduction of CCL22 expression in the tumor microenvironment (TME), as well as the expression of other immune-suppressive molecules such as IDO. Furthermore, vaccinated mice harbored an increased CD8+ T cell infiltration with a concomitant increase in M1/M2 ratio within the TME.ConclusionsThis study provides evidence that targeting CCL22 expressing cells by vaccination induces immune modulation in the TME, leading to augmentation of anti-tumor responses - thus provides a rationale for a novel immunotherapeutic approach in cancer.Disclosure InformationI. Lecoq: A. Employment (full or part-time); Modest; IO Biotech. K.L. Kopp: A. Employment (full or part-time); Modest; IO Biotech. R. Christensen: A. Employment (full or part-time); Modest; IO Biotech. E. Martinenaite: A. Employment (full or part-time); Modest; IO Biotech. A.W. Pedersen: A. Employment (full or part-time); Modest; IO Biotech. M.H. Andersen: A. Employment (full or part-time); Modest; IO Biotech.

scholarly journals P04.03 Immune modulatory vaccine directed against IDO1-expressing immune cells elicits T cell-mediated anti-tumor immunity and enhances anti-PD1 responses

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A37.2-A38
Author(s):  
S Dey ◽  
E Sutanto-Ward ◽  
KL Kopp ◽  
JB DuHadaway ◽  
A Mondal ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class I ◽  
Tumor Response ◽  
Ex Vivo ◽  
Class Ii ◽  
Class I ◽  
Peptide Vaccines ◽  
Ido1 Expression ◽  
Part Time

BackgroundIndoleamine 2,3-dioxygenase 1 (IDO1) is a tryptophan-catabolizing enzyme that contributes to immunoregulation at many levels, including suppressing effector T cells and inducing/activating regulatory T cells. Thus far, several therapeutic approaches to target IDO1 enzymatic activity have shown promise in preclinical models, however, results from the first major clinical trial were disappointing. The present study seeks to provide preclinical PoC data for the conceptually unique idea of developing an IDO1-targeted vaccine based on our earlier findings that humans exhibit intrinsic T cell reactivity against IDO1 epitopes1 suggesting the existence of a T cell-mediated, counter-regulatory mechanism directed against cells that express IDO1.Materials and MethodsIDO1-derived peptide vaccines were identified by measurement of vaccine-induced ex vivo response (IFNγ ELISpot) and demonstration of anti-tumor responses in CT26 tumor-bearing mice. To understand the vaccine’s mode of action, resected tumors were analyzed by immunofluorescence microscopy and flow cytometry.ResultsThe CT26 colon carcinoma model was selected for these studies based on evidence of high levels of IDO1 expression and responsiveness to IDO1 inhibition reported for these tumors. In silico-predicted H2d MHC class I and II-restricted IDO1 peptide sequences were tested and vaccine candidates were chosen after confirming ex vivo response and anti-tumor response in CT26. Therapeutic treatment of established CT26 tumors with MHC class I- and II-directed, IDO1-derived peptide vaccines elicited anti-tumor responses when administered alone, and the effect was further pronounced when combined, suggesting distinct mechanisms of action. In addition, a combination of IDO1 vaccine with anti-PD-1 antibody produced a combinatorial anti-tumor response beyond what was achieved with either agent alone. Consistent with this observation, adoptive transfer of isolated CD8+ T cells from class I and CD4+ T cells from class II peptide-vaccinated responder mice delayed tumor growth in treatment naïve mice. The class II-directed response was completely IDO1-dependent while the class I-directed response included an IDO1-independent component indicative of antigen spread. Examination into the tumors in vaccinated mice indicated that IDO1 vaccine treatment exerts its effect by selective reduction of IDO1 expression in the tumor microenvironment and concomitant expansion of activated CD4+ and CD8+ T cells.ConclusionsAs noted in humans, our data demonstrate that IDO1 is immunogenic in mice confirming that this endogenous protein is excluded from normal tolerance mechanisms. The observed immunotherapeutic efficacy of IDO1 peptide vaccines on their own and in combination with anti-PD-1 antibody support the rationale for ongoing clinical development of IDO1 peptide vaccine-based therapy. Future studies include further differentiation of the vaccine platform against other IDO1-targeting approaches, as well as decoding the underlying mechanism of cooperativity between anti-PD-1 antibody and IDO1 peptide vaccines.ReferenceSørensen RB, Hadrup SR, Svane IM, Hjortsø MC, Thor Straten P, Andersen MH. Indoleamine 2,3-dioxygenase specific, cytotoxic T cells as immune regulators. Blood 2011; 117(7): 2200–10Disclosure InformationS. Dey: None. E. Sutanto-Ward: None. K.L. Kopp: A. Employment (full or part-time); Significant; IO Biotech. J.B. DuHadaway: None. A. Mondal: None. I. Lecoq: A. Employment (full or part-time); Significant; IO Biotech. M. Zocca: A. Employment (full or part-time); Significant; IO Biotech. M.H. Andersen: A. Employment (full or part-time); Significant; IO Biotech. A.W. Pedersen: A. Employment (full or part-time); Significant; IO Biotech. A.J. Muller: F. Consultant/Advisory Board; Modest; IO Biotech.

scholarly journals 843 Development and engineering of human sialidase for degradation of immunosuppressive sialoglycans to treat cancer

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A884-A884
Author(s):  
Li Peng ◽  
Lizhi Cao ◽  
Sujata Nerle ◽  
Robert LeBlanc ◽  
Abhishek Das ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Cells ◽  
First Generation ◽  
Single Agent ◽  
Mouse Tumor ◽  
Cytokine Release ◽  
Tumor Models ◽  
Cell Immunity ◽  
Mouse Tumor Models

BackgroundSialoglycans, a type of glycans with a terminal sialic acid, have emerged as a critical glyco-immune checkpoint that impairs antitumor response by inhibiting innate and adaptive immunity. Upregulation of sialoglycans on tumors has been observed for decades and correlates with poor clinical outcomes across many tumor types. We previously showed that targeted desialylation of tumors using a bifunctional sialidase x antibody molecule, consisting of sialidase and a tumor-associated antigen (TAA)-targeting antibody, has led to robust single-agent efficacy in mouse tumor models. In addition to tumor cells, most immune cells present substantially more abundant sialoglycans than non-hematological healthy cells, which may also contribute to immunosuppression. Therefore, we studied the impact of immune cell desialylation and evaluated the therapeutic potential of a newly developed sialidase-Fc fusion (Bi-Sialidase), which lacks a TAA-targeting moiety and consists of engineered human neuraminidase 2 (Neu2) and human IgG1 Fc region, in preclinical mouse tumor models.MethodsThe first generation Neu2 variant was further optimized to improve titers and stability to constructed Bi-Sialidase. Bi-Sialidase’s desialylation potency and impact on immune responses were studied in vitro using various human immune functional assays, including T-cell activation, allogeneic mixed lymphocyte reaction, antibody-dependent cellular cytotoxicity, macrophages polarization/activation, neutrophil activation, and peripheral blood mononuclear cell (PBMC) cytokine release assays. We evaluated its antitumor efficacy in mouse tumor models. Bi-Sialidase’s safety profile was characterized by conducting rat and non-human primate (NHP) toxicology studies.ResultsThe optimized Bi-Sialidase achieved a titer of 2.5 g/L from a 15-day fed-batch Chinese hamster ovary cell culture; in contrast, the wild-type and first-generation Neu2 had no production or a low titer (<0.1 g/L) under similar conditions, respectively. We demonstrated that Bi-Sialidase led to dose-dependent desialylation of immune cells and potentiated T-cell immunity, without impacting NK, macrophage, or neutrophil activation by desialylating immune cells. Activated and exhausted T cells upregulated surface sialoglycans and Bi-Sialidase-mediated desialylation reinvigorated exhausted-like T cells as measured by IFNg production. Bi-Sialidase treatment also enhanced DC priming and activation of naïve T cells by desialylating both T cells and DCs. Furthermore, Bi-Sialidase showed single-agent antitumor activity in multiple mouse tumor models, including MC38, CT26, A20, and B16F10. Importantly, Bi-Sialidase did not cause cytokine release in human PBMC assays and was tolerated to up to 100 mg/kg in rats and NHPs, demonstrating a wide safety margin.ConclusionsBi-Sialidase with an optimized Neu2 offers a novel immunomodulatory approach to enhancing T-cell immunity by desialylating immunosuppressive sialoglycans for cancer treatment.

scholarly journals A Correlation Between Differentiation Phenotypes of Infused T Cells and Anti-Cancer Immunotherapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Hao Ren ◽  
Kunkun Cao ◽  
Mingjun Wang
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antitumor Immunity ◽  
Ex Vivo ◽  
T Cell Therapy ◽  
Production Methods ◽  
Anti Cancer ◽  
Status Differentiation ◽  
Differentiation Status

T-cell therapy, usually with ex-vivo expansion, is very promising to treat cancer. Differentiation status of infused T cells is a crucial parameter for their persistence and antitumor immunity. Key phenotypic molecules are effective and efficient to analyze differentiation status. Differentiation status is crucial for T cell exhaustion, in-vivo lifespan, antitumor immunity, and even antitumor pharmacological interventions. Strategies including cytokines, Akt, Wnt and Notch signaling, epigenetics, and metabolites have been developed to produce less differentiated T cells. Clinical trials have shown better clinical outcomes from infusion of T cells with less differentiated phenotypes. CD27+, CCR7+ and CD62L+ have been the most clinically relevant phenotypic molecules, while Tscm and Tcm the most clinically relevant subtypes. Currently, CD27+, CD62L+ and CCR7+ are recommended in the differentiation phenotype to evaluate strategies of enhancing stemness. Future studies may discover highly clinically relevant differentiation phenotypes for specific T-cell production methods or specific subtypes of cancer patients, with the advantages of precision medicine.

scholarly journals P03.02 Protein-based cancer vaccine combined with an oncolytic vaccine promotes potent antitumor immunity

2021 ◽  
Vol 9 (Suppl 1) ◽  
pp. A13.2-A14
Author(s):  
E Belnoue ◽  
K Das ◽  
M Rossi ◽  
T Hofer ◽  
S Danklmaier ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Oncolytic Virus ◽  
Antitumor Immunity ◽  
Checkpoint Blockade ◽  
Tumor Models ◽  
Tumor Associated Antigens ◽  
T Cell Infiltration ◽  
Part Time

BackgroundKISIMATM platform allows the development of protein-based cancer vaccines able to induce a potent, tumor-specific CD8 and CD4 T cells response. While the cell penetrating peptide and peptide agonist for Toll like receptor (TLR)-2 and TLR-4 confer, respectively, the cell delivery and self-adjuvanticity properties, the multiantigenic domain allows the targeting of different cancer antigens, resulting in anti-tumoral efficacy in different murine models. Oncolytic viruses exert their therapeutic effects by a prolonged oncolytic action and the associated intratumoral inflammation as well as general immune activation. Arming oncolytic virus with tumor associated antigens can additionally enhance the tumor-specific T cell portion and therefore positively affect the balance of antitumor versus antiviral immune responses. The protein vaccine KISIMATM and the recombinant oncolytic virus VSV-GP-TAA (vesicular stomatitis virus pseudotyped with LCMV GP expressing tumor-associated antigens) are both promising vaccine candidates that offer a new cancer vaccination opportunity when combined in heterologous prime-boost regimen.Materials and MethodsMice were vaccinated with subcutaneous (s.c.) injection of KISIMA-TAA vaccine and/or with intravenous injection of VSV-GP-TAA in different settings. Immunogenicity was assessed by measuring the peripheral antigen-specific response. Anti-tumoral efficacy as well as in depth monitoring of TILs and tumor microenvironment modulation were assessed following therapeutic vaccination in different tumor models. Additionally, transcriptome and immunohistochemistry analyses of the TC-1 tumor have been performed. Combination of heterologous prime-boost with checkpoint blockade PD-1 therapy has been assessed.ResultsPriming with KISIMA-TAA followed by VSV-GP-TAA boost induced a large pool of polyfunctional and persistent antigen-specific cytotoxic T cells in the periphery as well as within the tumor in several tumor models. Frequencies of antigen specific T cells are significantly higher than the respective homologous vaccinations. Additionally, transcriptome analysis of a cold tumor model revealed profound changes in the tumor microenvironment upon heterologous vaccination, including a strong upregulation of gene signatures of several pro-inflammatory cytokines and chemokines required for antitumor immunity along with dendritic and T cell trafficking and activation. This was corroborated by flow-cytometric analysis of tumor-infiltrating leukocytes showing massive CD8+ and CD4+ T cell infiltration as well as repolarization of M2-like macrophages towards M1-phenotype. The presence of the CD8+ T cells within the tumor core was confirmed by immunohistochemistry analysis. Moreover, combining heterologous vaccination with checkpoint blockade further improved its therapeutic efficacy and the number of long-term survivors.ConclusionsThe KISIMA/VSV-GP heterologous prime-boost approach holds great promise for patients with primary or acquired resistance to checkpoint blockade due to its ability to induce tumor-specific T cell, improve T cell infiltration and increase tumor inflammation, even in tumors with limited permissivity for the oncolytic virus.Disclosure InformationE. Belnoue: A. Employment (full or part-time); Significant; AMAL Therapeutics SA. K. Das: None. M. Rossi: A. Employment (full or part-time); Significant; AMAL Therapeutics SA. T. Hofer: None. S. Danklmaier: None. T. Nolden: A. Employment (full or part-time); Significant; Viratherapeutics GmbH. L. Schreiber: None. K. Angerer: None. J. Kimpel: None. S. Hoegler: None. L. Kenner: None. D. von Laer: None. K. Elbers: A. Employment (full or part-time); Significant; Viratherapeutics GmbH. G. Wollmann: None. M. Derouazi: A. Employment (full or part-time); Significant; AMAL Therapeutics SA.

scholarly journals The PI-3-Kinase P110α Catalytic Subunit of T Lymphocytes Modulates Collagen-Induced Arthritis

2021 ◽  
Vol 22 (12) ◽  
pp. 6405
Author(s):  
María Montes-Casado ◽  
Gloria Ojeda ◽  
Gabriel Criado ◽  
José M. Rojo ◽  
Pilar Portolés
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
Immune Modulation ◽  
Ex Vivo ◽  
Adaptive Immune Response ◽  
Collagen Induced Arthritis ◽  
Akt Phosphorylation ◽  
Specific Deletion

The phosphatidylinositol 3-kinase (PI3K) family of enzymes plays a determinant role in inflammation and autoimmune responses. However, the implication of the different isoforms of catalytic subunits in these processes is not clear. Rheumatoid arthritis (RA) is a chronic, systemic autoimmune inflammatory disease that entails innate and adaptive immune response elements in which PI3K is a potential hub for immune modulation. In a mouse transgenic model with T-cell-specific deletion of p110α catalytic chain (p110α−/−ΔT), we show the modulation of collagen-induced arthritis (CIA) by this isoform of PI3K. In established arthritis, p110α−/−ΔT mice show decreased prevalence of illness than their control siblings, higher IgG1 titers and lower levels of IL-6 in serum, together with decreased ex vivo Collagen II (CII)-induced proliferation, IL-17A secretion and proportion of naive T cells in the lymph nodes. In a pre-arthritis phase, at 13 days post-Ag, T-cell-specific deletion of p110α chain induced an increased, less pathogenic IgG1/IgG2a antibodies ratio; changes in the fraction of naive and effector CD4+ subpopulations; and an increased number of CXCR5+ T cells in the draining lymph nodes of the p110α−/−ΔT mice. Strikingly, T-cell blasts in vitro obtained from non-immunized p110α−/−ΔT mice showed an increased expression of CXCR5, CD44 and ICOS surface markers and defective ICOS-induced signaling towards Akt phosphorylation. These results, plus the accumulation of cells in the lymph nodes in the early phase of the process, could explain the diminished illness incidence and prevalence in the p110α−/−ΔT mice and suggests a modulation of CIA by the p110α catalytic chain of PI3K, opening new avenues of intervention in T-cell-directed therapies to autoimmune diseases.

scholarly journals 1003 Malignant T cells inhibit anti-cancer immunity in cutaneous T cell lymphoma

2018 ◽  
Vol 138 (5) ◽  
pp. S170
Author(s):  
D. Ignatova ◽  
Y. Chang ◽  
A. Cozzio ◽  
R. Dummer ◽  
L.E. French ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Cutaneous T Cell Lymphoma ◽  
Cancer Immunity ◽  
Anti Cancer ◽  
Malignant T Cells

scholarly journals A Palette of Cytokines to Measure Anti-Tumor Efficacy of T Cell-Based Therapeutics

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 821
Author(s):  
Prathyaya Ramesh ◽  
Rohan Shivde ◽  
Dinesh Jaishankar ◽  
Diana Saleiro ◽  
I. Caroline Le Poole
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Immune Responses ◽  
Cd8 T Cells ◽  
Mechanisms Of Action ◽  
Immune Monitoring ◽  
Cancer Immunity ◽  
Anti Cancer ◽  
Ifn Γ

Cytokines are key molecules within the tumor microenvironment (TME) that can be used as biomarkers to predict the magnitude of anti-tumor immune responses. During immune monitoring, it has been customary to predict outcomes based on the abundance of a single cytokine, in particular IFN-γ or TGF-β, as a readout of ongoing anti-cancer immunity. However, individual cytokines within the TME can exhibit dual opposing roles. For example, both IFN-γ and TGF-β have been associated with pro- and anti-tumor functions. Moreover, cytokines originating from different cellular sources influence the crosstalk between CD4+ and CD8+ T cells, while the array of cytokines expressed by T cells is also instrumental in defining the mechanisms of action and efficacy of treatments. Thus, it becomes increasingly clear that a reliable readout of ongoing immunity within the TME will have to include more than the measurement of a single cytokine. This review focuses on defining a panel of cytokines that could help to reliably predict and analyze the outcomes of T cell-based anti-tumor therapies.

Role of the immunoglobulin constant region in the antitumor activity of antibodies to cytotoxic T-lymphocyte antigen-4 (CTLA-4).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 9055-9055
Author(s):  
Alan J. Korman ◽  
John Engelhardt ◽  
Vafa Shahabi ◽  
Roumyana Yordanova ◽  
Karla Henning ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antitumor Activity ◽  
Phase Iii ◽  
Mouse Tumor ◽  
Constant Region ◽  
Tumor Site ◽  
Tumor Models ◽  
Mouse Tumor Models

9055 Background: Anti-CTLA-4 therapy enhances antitumor T-cell responses by both cell-intrinsic and cell-extrinsic mechanisms. Effector T-cell (Teff) activation is increased directly by interfering with CTLA-4-B7 interactions that negatively regulate T cells and by interfering with CTLA-4 expressed on regulatory T cells (Tregs), which function to inhibit immune responses. To analyze in greater detail the mechanism of action of anti-CTLA-4 antibodies (Abs), we examined the role of the immunoglobulin constant region in the antitumor activity of anti-CTLA-4 Abs in mouse tumor models. Methods: The activity of anti-CTLA-4 Abs with different mouse IgG constant regions were compared in several mouse tumor models, and intratumoral and peripheral T cells were analyzed by FACS. DNA samples from 488 patients with metastatic melanoma who received ipilimumab in a phase III clinical trial, MDX010-20, were analyzed for polymorphisms in the IgG fragment c receptor (FcR) at FCGR3A (V158F) and FCGR2A (H131R) loci. Results: In subcutaneous MC38 and CT26 colon tumor models, an anti-CTLA-4 Ab containing the mouse IgG2a constant region exhibited enhanced antitumor activity compared to an anti-CTLA-4 Ab containing the IgG2b constant region, while anti-CTLA-4 Abs containing mouse IgG1 or a mutated mouse IgG1 D265A constant region showed no activity. Anti-CTLA-4-IgG2a caused a dramatic reduction of Tregs at the tumor site that resulted in a greater Teff/Treg ratio. In contrast, all isotypes resulted in expansion of Tregs in the periphery. These results point to an important role for FcR in the action of anti-CTLA-4 Abs. In patients from study MDX010-20, there was no association between the 2 FcR polymorphisms (FCGR3A and FCGR2A) and overall survival. Conclusions: These preclinical studies reveal a novel dual activity of anti-CTLA-4 Abs consisting of intratumoral reduction of Tregs together with activation of Teff cells. This effect is mediated by the constant region and is presumably due to antibody-dependent cellular cytotoxicity. The data suggest that FcR-bearing cells at the tumor site, as well as the presence of intratumoral Tregs, may be important factors in the antitumor activity of anti-CTLA-4 Abs.

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